We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined.
We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks.
The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.
Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects.
Myoclonus may occur after hypoxia. In 1963, Lance and Adams described persistent myoclonus with other features after hypoxia. However, myoclonus occurring immediately after hypoxia may demonstrate different syndromic features from classic Lance–Adams syndrome (LAS). The aim of this review is to provide up-to-date information about the spectrum of myoclonus occurring after hypoxia with emphasis on neurophysiological features.
A literature search was performed on PubMed database from 1960 to 2015. The following search terms were used: “myoclonus,” “post anoxic myoclonus,” “post hypoxic myoclonus,” and “Lance Adams syndrome.” The articles describing clinical features, neurophysiology, management, and prognosis of post-hypoxic myoclonus cases were included for review.
Several reports in the literature were separated clinically into “acute post-hypoxic myoclonus,” which occurred within hours of severe hypoxia, and “chronic post-hypoxic myoclonus,” which occurred with some recovery of mental status as the LAS. Acute post-hypoxic myoclonus was generalized in the setting of coma. Chronic post-hypoxic myoclonus presented as multifocal cortical action myoclonus that was significantly disabling. There was overlap of neurophysiological findings for these two syndromes but also different features. Treatment options for these two distinct clinical–neurophysiologic post-hypoxic myoclonus syndromes were approached differently.
The review of clinical and neurophysiological findings suggests that myoclonus after hypoxia manifests in one or a combination of distinct syndromes: acute and/or chronic myoclonus. The mechanism of post-hypoxic myoclonus may arise either from cortical and/or subcortical structures. More research is needed to clarify mechanisms and treatment of post-hypoxic myoclonus.
Lance–Adams syndrome; myoclonus; post-hypoxic myoclonus; post-anoxic myoclonus; neurophysiology
To determine what differences exist in graph theory network measures derived from electroencephalography (EEG), between Parkinson's disease (PD) patients who are cognitively normal (PD-CN) and matched healthy controls; and between PD-CN and PD dementia (PD-D).
EEG recordings were analyzed via graph theory network analysis to quantify changes in global efficiency and local integration. This included minimal spanning tree analysis. T-tests and correlations were used to assess differences between groups and assess the relationship with cognitive performance.
Network measures showed increased local integration across all frequency bands between Control and PD-CN; in contrast, decreased local integration occurred in PD-D when compared to PD-CN in the alpha1 frequency band. Differences found in PD-MCI mirrored PD-D. Correlations were found between network measures and assessments of global cognitive performance in PD.
Our results reveal distinct patterns of band and network measure type alteration and breakdown for PD, as well as with cognitive decline in PD.
These patterns suggest specific ways that interaction between cortical areas becomes abnormal and contributes to PD symptoms at various stages. Graph theory analysis by EEG suggests that network alteration and breakdown are robust attributes of PD cortical dysfunction pathophysiology.
Parkinson's disease; dementia; biomarker; EEG; network, synucleinopathy; pathology
High-density electroencephalography was used to evaluate cortical activity during speech comprehension via a sentence verification task. Twenty-four participants assigned true or false to sentences produced with 3 noise-vocoded channel levels (1-unintelligible, 6-decipherable, 16-intelligible), during simultaneous EEG recording. Participant data were sorted into higher- (HP) and lower-performing (LP) groups. The identification of a late-event related potential for LP listeners in the intelligible condition and in all listeners when challenged with a 6-Ch signal supports the notion that this induced potential may be related to either processing degraded speech, or degraded processing of intelligible speech. Different cortical locations are identified as neural generators responsible for this activity; HP listeners are engaging motor aspects of their language system, utilizing an acoustic-phonetic based strategy to help resolve the sentence, while LP listeners do not. This study presents evidence for neurophysiological indices associated with more or less successful speech comprehension performance across listening conditions.
EEG; speech; perception; disordered; intelligibility; listening strategy
Olfactory dysfunction in Parkinson's disease (PD) is well-established and may represent one of the earliest signs of the disease.
Objective & methods
The objective of this study was to evaluate the relationship of olfactory dysfunction, using the University of Pennsylvania Smell Identification Test (UPSIT), to clinical and pathological parameters of clinicopathologically diagnosed PD (n = 10), incidental Lewy body disease (ILBD) (n = 13), and identically assessed controls who lacked a neurodegenerative disease (n = 69).
Mean UPSIT scores were significantly lower in PD (16.3, p < 0.001) and ILBD (22.2, p = 0.004) compared to controls (27.7). Using an UPSIT cutoff score of <22 (the 15th percentile) the sensitivity for detecting PD was 9/10 (90%) and ILBD 6/13 (46%), while the specificity was 86% (Controls with score of <22 = 10/69).
= These results add to the growing body of evidence suggesting that olfactory testing could be useful as a screening tool for identifying early, pre-motor PD.
Parkinson's disease; Hyposmia; Incidental Lewy body disease
To identify a panel of peripheral inflammatory/immune mediators that could discriminate Parkinson disease with dementia (PDD) from Parkinson disease (PD) without dementia.
Plasma samples from 52 patients with PD and 22 patients with PDD were prepared from freshly collected blood following an institutional review board–approved protocol. A total of 160 proteins were measured using a multiplex antibody array. Plasma α-synuclein levels were analyzed by an electrochemiluminescence immunoassay. The main objective of the statistical analyses was to identify PDD discriminants using the plasma protein profile alone or in combination with age.
The PD and PDD groups differed significantly in cognitive measurements (Mini-Mental State Examination, Auditory Verbal Learning Test-A7, and Clinical Dementia Rating) and age. The age-adjusted levels of thymus and activation-regulated chemokine (TARC) and platelet-derived growth factor (PDGF)-AA were significantly different between disease groups. The levels of plasma α-synuclein significantly correlated with 26 proteins; among them, PDGF-BB, TARC, PDGF-AA, and epidermal growth factor were the highest. Linear discriminant analysis with leave-one-out cross-validation identified a 14-protein panel with age as discriminants of PDD (96% sensitivity, 89% specificity, area under the curve = 0.9615).
We showed that multiple proteins that are mediators of growth/trophic and immune response-related pathways had discriminatory power for identifying PDD in patients with PD. Validation of this discovery-based study in longitudinal population-based studies is warranted.
Classification of evidence:
This study provides Class III evidence that a 14-protein panel plasma assay combined with age has a sensitivity of 96% and a specificity of 89% for PDD.
The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer’s disease, Parkinson’s disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer’s Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson’s Research. The Program has made rapid autopsy a priority, with a 3.0-hour median postmortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.
aging; Alzheimer’s disease; autopsy; biobank; biospecimen; brain bank; cancer; freeze-thaw; Parkinson’s disease; pathology; post-mortem interval; RNA
Previous research has linked complex or formed visual hallucinations (VH) to Lewy-type alpha-synucleinopathy (LTS) in neocortical and limbic areas. As Alzheimer’s disease pathology often co-occurs with LTS, we questioned whether this pathology - amyloid plaques and neurofibrillary tangles - might also be linked to VH.
We performed a semi-quantitative neuropathological study across brainstem, limbic, and cortical structures in subjects with a documented clinical history of VH and a clinicopathological diagnosis of Parkinson’s disease (PD), Alzheimer’s disease (AD), or dementia with Lewy bodies (DLB). 173 subjects – including 50 with VH and 123 without VH – were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical variables examined included the Mini-mental State Exam, Hoehn & Yahr stage, and total dopaminergic medication dose. Neuropathological variables examined included total and regional LTS and plaque and tangle densities.
A significant relationship was found between the density of LTS and the presence of VH in PD, AD, and DLB. Plaque and tangle densities also were associated with VH in PD (p=.003 for plaque and p=.004 for tangles) but not in AD, where densities were high regardless of the presence of hallucinations. Furthermore, with DLB cases excluded, comorbidity of PD and AD was significantly more prevalent among subjects +VH than subjects −VH (p<.001).
These findings suggest that both AD and PD neuropathology contribute to the pathogenesis of VH. Incident VH could be predictive of concomitant AD/PD pathology even when criteria are not met for a second diagnosis.
visual hallucinations; hallucinations; psychosis; Alzheimer’s disease; Parkinson’s disease
Orthostatic tremor (OT) is defined by the presence of a high-frequency (13–18 Hz) tremor of the legs upon standing associated with a feeling of unsteadiness. However, some patients have discharge frequencies of <13 Hz, so-called “slow OT”. The aim of this study was to characterize patients with unsteadiness upon standing found to have <13 Hz tremor discharges on neurophysiologic testing.
A retrospective review was performed on all subjects with a diagnosis of OT who were referred to the Mayo Clinic, Scottsdale, AZ, between 1999 and 2013 for confirmation using neurophysiology.
Fourteen of 28 subjects (50%) had OT discharges of <13 Hz, of whom eight had frequencies of <10 Hz and six had frequencies of 10–13 Hz. Lower frequency discharges tended to have a broader spectral peak, greater variability in discharge duration, and lower inter-muscular coherence. Subjects with <13 Hz OT had shorter mean disease duration at time of neurophysiology testing (2.00 years in <10 Hz group, 7.96 years 10–13 Hz group, and 11.43 years >13 Hz; p = 0.002). The proportion of subjects who experienced gait unsteadiness (85.7% vs. 66.6% vs. 21.4%; p = 0.016), falls (37.5% vs. 50% vs. 0%; p = 0.010), and had abnormal gait on examination (71.4% vs. 66.0% vs. 14.3%; p = 0.017) was greater in those with low and intermediate frequencies.
Slow tremor electromyography frequencies (<13 Hz) may characterize a substantial proportion of patients labeled as OT. These subjects may have greater gait involvement and higher likelihood of falls leading to earlier presentation to subspecialty care.
Orthostatic tremor; neurophysiology
Although there are studies investigating the pathologic origins of mild cognitive impairment (MCI), they have revolved around comparisons to normal elderly individuals or those with Alzheimer’s disease (AD) or other dementias. There are few studies directly comparing the comprehensive neuropathology of amnestic (aMCI) and nonamnestic (naMCI) MCI.
The database of the Brain and Body Donation Program (www.brainandbodydonationprogram.org), a longitudinal clinicopathological study of normal aging and neurodegenerative disorders, was queried for subjects who were carrying a diagnosis of aMCI or naMCI at the time of autopsy. Neuropathological lesions, including neuritic plaques, neurofibrillary tangles (NFTs), Lewy bodies (LBs), infarcts, cerebral white matter rarefaction (CWMR), cerebral amyloid angiopathy (CAA), and concurrent major clinicopathological diagnoses, including Parkinson’s disease (PD) were analyzed.
Thirty four subjects with aMCI and 15 naMCI met study criteria. Subjects with aMCI were older at death (88 vs. 83 years of age, p = 0.03). Individuals with naMCI had higher densities of LBs within the temporal lobe (p = 0.04) while subjects with aMCI had a propensity for increased NFTs in parietal and temporal lobes (p values = 0.07). After adjusting for age at death, the only significant difference was greater densities of temporal lobe NFTs within the aMCI group. Other regional pathology scores for plaques, NFTs, and LBs were similar between groups. Subjects met clinico-pathological criteria for co-existent PD in 24 % aMCI and 47 % naMCI while neuropathological criteria for AD were met in equal percentages of aMCI and of naMCI cases (53 %); these proportional differences were not significant (p values > 0.35). Furthermore, regardless of amnestic status, there was a greater presence of CAA (71 % of MCI with executive dysfunction vs. 39 % without p = 0.03) and a greater presence of CWMR (81 % of MCI with executive dysfunction and 54 % without p = 0.046) in MCI cases with executive dysfunction.
No single pathologic entity strongly dichotomized MCI groups, perhaps due to the pathologic heterogeneity found within both entities. However, these data suggest the possibility for naMCI to have a propensity for increased LBs and aMCI for increased NFTs in select anatomic regions.
Dysphagia is common in Parkinson’s disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia.
Alpha-synuclein histopathology; Dysphagia; Lewy-type synucleinopathy; Parkinson’s disease; Peripheral sensory nerves; Upper aerodigestive tract
Determine diagnostic accuracy of a clinical diagnosis of Parkinson disease (PD) using neuropathologic diagnosis as the gold standard.
Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to determine the predictive value of a clinical PD diagnosis, using 2 clinical diagnostic confidence levels, PossPD (never treated or not clearly responsive) and ProbPD (responsive to medications). Neuropathologic diagnosis was the gold standard.
Based on first visit, 9 of 34 (26%) PossPD cases had neuropathologically confirmed PD while 80 of 97 (82%) ProbPD cases had confirmed PD. PD was confirmed in 8 of 15 (53%) ProbPD cases with <5 years of disease duration and 72 of 82 (88%) with ≥5 years of disease duration. Using final diagnosis at time of death, 91 of 107 (85%) ProbPD cases had confirmed PD. Clinical variables that improved diagnostic accuracy were medication response, motor fluctuations, dyskinesias, and hyposmia.
Using neuropathologic findings of PD as the gold standard, this study establishes the novel findings of only 26% accuracy for a clinical diagnosis of PD in untreated or not clearly responsive subjects, 53% accuracy in early PD responsive to medication (<5 years' duration), and >85% diagnostic accuracy of longer duration, medication-responsive PD. Caution is needed when interpreting clinical studies of PD, especially studies of early disease that do not have autopsy confirmation. The need for a tissue or other diagnostic biomarker is reinforced.
Classification of evidence:
This study provides Class II evidence that a clinical diagnosis of PD identifies patients who will have pathologically confirmed PD with a sensitivity of 88% and specificity of 68%.
Existing reports on the frequencies of neurodegenerative diseases are typically based on clinical diagnoses. We sought to determine these frequencies in a prospectively-assessed, community-based autopsy series. Included subjects had normal cognitive and movement disorder assessments at study entry. Of the 119 cases meeting these criteria, 52% were female, median age of study entry was 83.5 years (range 67 to 99), and median duration from first visit until death was 4.3 years (range 0-10). At autopsy a clinico-neuropathological diagnosis was made in 30 cases (25%). Clinicopathological diagnoses included 20 (17%) with Alzheimer's disease (AD), 7 (6%) with vascular dementia, 4 (3%) with progressive supranuclear palsy, (1; 0.8%) with dementia with Lewy bodies, (1; 0.8%) with corticobasal degeneration and (1; 0.8%) with multiple system atrophy. Of those 87 subjects (73%) still clinically normal at death, 33 (38%) had extensive AD pathology (pre-clinical AD), 17 (20%) had incidental Lewy bodies and 4 (5%) had incidental pathology consistent with progressive supranuclear palsy. Diagnoses are not mutually exclusive. Although limited by a relatively small sample size, the neuropathological outcome of these initially normal elderly subjects represents a rough estimate of the incidence of these neurodegenerative conditions over a defined time period.
Alzheimer's disease; progressive supranuclear palsy; vascular dementia; Parkinson's disease; dementia with Lewy bodies; pathology; epidemiology
Myoclonus creates significant disability for patients. This symptom or sign can have many different etiologies, presentations, and pathophysiological mechanisms. A thorough evaluation for the myoclonus etiology is critical for developing a treatment strategy. The best etiological classification scheme is a modified version from that proposed by Marsden et al. in 1982. Clinical neurophysiology, as assessed by electromyography and electroencephalography, can be used to classify the pathophysiology of the myoclonus using a neurophysiology classification scheme. If the etiology of the myoclonus cannot be reversed or treated, then symptomatic treatment of the myoclonus itself may be warranted. Unfortunately, there are few controlled studies for myoclonus treatments. The treatment strategy for the myoclonus is best derived from the neurophysiology classification scheme categories: 1) cortical, 2) cortical–subcortical, 3) subcortical–nonsegmental, 4) segmental, and 5) peripheral. A cortical physiology classification is most common. Levetiracetam is suggested as first-line treatment for cortical myoclonus, but valproic acid and clonazepam are commonly used. Cortical–subcortical myoclonus is the physiology demonstrated by myoclonic seizures, such as in primary epileptic myoclonus (e.g., juvenile myoclonic epilepsy). Valproic acid has demonstrated efficacy in such epileptic syndromes with other medications providing an adjunctive role. Clonazepam is used for subcortical–nonsegmental myoclonus, but other treatments, depending on the syndrome, have been used for this physiological type of myoclonus. Segmental myoclonus is difficult to treat, but clonazepam and botulinum toxin are used. Botulinum toxin is used for focal examples of peripheral myoclonus. Myoclonus treatment is commonly not effective and/or limited by side effects.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-013-0216-3) contains supplementary material, which is available to authorized users.
Myoclonus; Seizure; Epilepsy; Treatment; EEG; EMG
Evidence of inflammation has been consistently associated with pathology in Parkinson's disease (PD)-affected brains, and has been suggested as a causative factor. Dopaminergic neurons in the substantia nigra (SN) pars compacta, whose loss results in the clinical symptoms associated with PD, are particularly susceptible to inflammatory damage and oxidative stress. Inflammation in the striatum, where SN dopaminergic neurons project, is also a feature of PD brains. It is not known whether inflammatory changes occur first in striatum or SN. Many animal models of PD have implicated certain inflammatory molecules with dopaminergic cell neuronal loss; however, there have been few studies to validate these findings by measuring the levels of these and other inflammatory factors in human PD brain samples. This study also included samples from incidental Lewy body disease (ILBD) cases, since ILBD is considered a non-symptomatic precursor to PD, with subjects having significant loss of tyrosine hydroxylase-producing neurons. We hypothesized that there may be a progressive change in key inflammatory factors in ILBD samples intermediate between neurologically normal and PD. To address this, we used a quantitative antibody-array platform (Raybiotech-Quantibody arrays) to measure the levels of 160 different inflammation-associated cytokines, chemokines, growth factors, and related molecules in extracts of SN and striatum from clinically and neuropathologically characterized PD, ILBD, and normal control cases. Patterns of changes in inflammation and related molecules were distinctly different between SN and striatum. Our results showed significantly different levels of interleukin (IL)-5, IL-15, monokine induced by gamma interferon, and IL-6 soluble receptor in SN between disease groups. A different panel of 13 proteins with significant changes in striatum, with IL-15 as the common feature, was identified. Although the ability to detect some proteins was limited by sensitivity, patterns of expression indicated involvement of certain T-cell cytokines, vascular changes, and loss of certain growth factors, with disease progression. The results demonstrate the feasibility of profiling inflammatory molecules using diseased human brain samples, and have provided additional targets to validate in relation to PD pathology.
inflammation; pathology; cytokines; antibody array; dopaminergic cell loss; Parkinson's disease; microglia; astrocytes
Data regarding autonomic function in restless legs syndrome (RLS) is limited to heart rate and blood pressure changes in cases having periodic limb movements (PLMS).
We compared autonomic symptoms of 49 subjects with RLS vs. 291 Controls using the SCOPA-Autonomic questionnaire (23 items in six domains scored 0–3). The total score and domain scores were transformed to 0 to 100 points. Subjects with neurodegenerative disorders (i.e. dementia, parkinsonism) were excluded.
The RLS group was younger (mean±SD 77.9 ± 8.0 vs. 80.5 ± 7.9 yrs, p=.03) and had more women (84% vs. 69%, p=.04). The mean SCOPA-Aut Total score was higher in the RLS group compared with Controls (20 ± 11 vs. 16 ± 9, p= .005). Additionally the RLS group had abnormalities in GI, cardiovascular, and pupillomotor domains. When comparing the percentage of subjects with any complaint on individual questions (score of ≥ 1) the RLS group had a greater number of subjects with sialorrhea, constipation, early abdominal fullness, lightheadedness when standing, and heat intolerance.
Autonomic complaints, especially GI, cardiovascular, and oversensitivity to light, are significantly increased in subjects with RLS. Causes for autonomic dysfunction in RLS require further investigation.
Restless Leg Syndrome; Autonomic symptoms
Hippocampal sclerosis (HS) is a neuropathological finding that frequently occurs with pathologies, such as Alzheimer's disease (AD). Prevalence estimates of HS in autopsy-confirmed dementia samples have varied between 0.4% and 24.5%. However, the prevalence of HS within other pathologic groups has not been well characterized.
Utilizing a sample of 910 prospectively followed and clinicopathologically confirmed dementia cases, we determined the prevalence of HS among the sample and within specific pathologic groups. HS prevalence of the sample was compared to reported HS prevalence rates in other autopsy-confirmed dementia samples.
The age range of the sample was 43 to 106 years, with a mean of 81.49±8.45. Of the 910 cases, 505 were male and 405 were female. For the entire sample, the average educational level was 14.59±2.65years. Of the 910 individuals, 47 (5.16%) cases had HS pathology present at autopsy. Among the 561 AD cases, 26 (4.43%) had HS pathology present. The frontotemporal dementia (FTD)/Pick's group had the highest percentage of cases with HS pathology (23.08%) followed by primary progressive aphasia (PPA) (16.67%) and Parkinson's disease with dementia (PDD) (5.34%). The HS prevalence rate of this study was not significantly different from all but 2 studies.
The prevalence of HS pathology in this sample of autopsy-confirmed dementia cases was similar to other reported HS prevalence rates. This study is the first to report the presence of HS pathology in PDD cases.
hippocampal sclerosis; dementia; neuropathology; TDP-43; Alzheimer's disease; Parkinson's disease
Dysphagia is very common in patients with Parkinson’s disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Unfortunately, current therapies are largely ineffective for dysphagia. As pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD for Lewy pathology. Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined: the glossopharyngeal nerve (IX); the pharyngeal sensory branch of the vagus nerve (PSB-X); and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect potential Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was significantly greater in PD subjects with documented dysphagia compared to those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in the IX and PSBX. These findings suggest that pharyngeal sensory nerves are directly affected by the pathologic process of PD. This anatomic pathology may decrease pharyngeal sensation impairing swallowing and airway protective reflexes, thereby contributing to dysphagia and aspiration.
Alpha-synuclein aggregates; Dysphagia; Glossopharyngeal nerve; Immunohistochemistry; Internal superior laryngeal nerve; Lewy neurites; Nerve degeneration; Parkinson disease; Peripheral nervous system; Pharyngeal sensory nerves; Pharynx; Swallowing; Vagus nerve
This study is the third in a series that has explored the source of intelligibility decrement in dysarthria by jointly considering signal characteristics and the cognitive–perceptual processes employed by listeners. A paradigm of lexical boundary error analysis was used to examine this interface by manipulating listener constraints with a brief familiarization procedure. If familiarization allows listeners to extract relevant segmental and suprasegmental information from dysarthric speech, they should obtain higher intelligibility scores than nonfamiliarized listeners, and their lexical boundary error patterns should approximate those obtained in misperceptions of normal speech. Listeners transcribed phrases produced by speakers with either hypokinetic or ataxic dysarthria after being familiarized with other phrases produced by these speakers. Data were compared to those of nonfamiliarized listeners [Liss et al., J. Acoust. Soc. Am. 107, 3415–3424 (2000)]. The familiarized groups obtained higher intelligibility scores than nonfamiliarized groups, and the effects were greater when the dysarthria type of the familiarization procedure matched the dysarthria type of the transcription task. Remarkably, no differences in lexical boundary error patterns were discovered between the familiarized and nonfamiliarized groups. Transcribers of the ataxic speech appeared to have difficulty distinguishing strong and weak syllables in spite of the familiarization. Results suggest that intelligibility decrements arise from the perceptual challenges posed by the degraded segmental and suprasegmental aspects of the signal, but that this type of familiarization process may differentially facilitate mapping segmental information onto existing phonological categories.
The ability to understand how Parkinson’s disease (PD) neurodegeneration leads to cortical dysfunction will be critical for developing therapeutic advances in PD dementia (PD-D). The overall purpose of this project was to study the small amplitude cortical myoclonus in PD as an in vivo model of focal cortical dysfunction secondary to PD neurodegeneration. The objectives were to test the hypothesis that cortical myoclonus in PD is linked to abnormal levels of α-synuclein in primary motor cortex and to define its relationship to various biochemical, clinical, and pathological measures.
Primary motor cortex was evaluated for 11 PD subjects with (PD+Myoclonus group) and 8 without (PD group) electrophysiologically confirmed cortical myoclonus who had premortem movement and cognitive testing. Similarly assessed 9 controls were used for comparison. Measurements for α-synuclein, Aβ-42 peptide, and other biochemical measures were made in primary motor cortex.
A 36% increase in α-synuclein was found in the motor cortex of PD+Myoclonus cases when compared to PD without myoclonus. This occurred without significant differences in insoluble α-synuclein, phosphorylated to total α-synuclein ratio, or Aβ-42 peptide levels. Higher total motor cortex α-synuclein levels significantly correlated with the presence of cortical myoclonus but did not correlate with multiple clinical or pathological findings.
These results suggest an association between elevated α-synuclein and the dysfunctional physiology arising from the motor cortex in PD+Myoclonus cases. Alzheimer’s disease pathology was not associated with cortical myoclonus in PD. Cortical myoclonus arising from motor cortex is a model to study cortical dysfunction in PD.
Parkinson’s disease (PD) is a neurodegenerative disease primarily characterized by cardinal motor symptoms and central nervous system pathology. As current drug therapies can often stabilize these cardinal motor symptoms attention has shifted to the other motor and non-motor symptoms of PD which are resistant to drug therapy. Dysphagia in PD is perhaps the most important drug resistant symptom as it leads to aspiration and pneumonia, the leading cause of death. Here, we present direct evidence for degeneration of the pharyngeal motor nerves in PD. In this study, we examined the cervical vagal (X) nerve, pharyngeal branch of the X nerve (Ph-X), and pharyngeal plexus innervating the pharyngeal muscles in 14 postmortem specimens, 10 subjects with PD and 4 age-matched control subjects. Synucleinopathy in the pharyngeal nerves was detected using an immunohistochemical method for phosphorylated α-synuclein. α-Synuclein aggregates were revealed in the X nerve and Ph-X and immunoreactive intramuscular nerve twigs and axon terminals within the neuromuscular junctions were identified in all the PD subjects and in none of the controls. These findings indicate that the motor nervous system of the pharynx is involved in the pathological process of PD. Notably, PD subjects with dysphagia had a higher density of α-synuclein aggregates in the pharyngeal nerves as compared with those without dysphagia. Motor involvement of the pharynx in PD appears to be one of the factors leading to oropharyngeal dysphagia commonly seen in PD patients.
α-Synuclein aggregates; Dysphagia; Immunohistochemistry; Intramuscular nerve twigs; Lewy bodies; Lewy neurites; Motor nerve; Nerve degeneration; Parkinson’s disease; Peripheral nervous system; Pharyngeal constrictor muscles; Pharyngeal plexus; Swallowing; Upper esophageal sphincter; Vagus nerve
Modifications of α-synuclein resulting in changes in its conformation are considered to be key pathological events for Lewy body diseases (LBD), which include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). We have previously described a histopathological Unified Staging System for LBD that classifies the spread of α-synuclein phosphorylated at serine 129 (pS129-α-synuclein) from olfactory bulb to brainstem or limbic regions, and finally neocortex. Lewy bodies and Lewy neurites are highly enriched in pS129-α-synuclein. Increased formation of pS129-α-synuclein changes its solubility properties enhancing its tendency to aggregate and disrupt normal function. As in vitro and animal studies have shown that inhibiting formation of pS129-α-synuclein can prevent toxic consequences, this has become one of the therapeutic targets for LBD. However, detailed biochemical descriptions of the changes in pS129-α-synuclein properties in diseased human brains are needed to further our understanding of how these might contribute to molecular pathogenesis. In this study, we used 130 separate brain samples from cingulate cortex (limbic cortex) and 131 from temporal cortex (neocortex) that had been staged according to our Unified Staging System to examine progressive changes in properties of pS129-α-synuclein with the formation of progressively more severe histological Lewy-type pathology. The brain samples from these staged cases had been separated into cytosol-enriched, membrane-enriched (detergent soluble) and insoluble (ureas/SDS soluble) fractions. We also characterized the nature and appearance of higher molecular weight forms of pS129-α-synuclein. The major species was the 16 kD monomeric form; this accumulated with increasing stage with a large increase in Stage IV samples. By comparing two brain regions, we showed higher accumulation of insoluble pS129-α-synuclein in cingulate cortex, where histological deposits occur first, than in temporal cortex in samples with advanced (Stage IV) LB pathology.
Western blots; Parkinson’s disease; antibodies; fractionation; post-translational modification; postmortem brain tissue; dementia with Lewy bodies; incidental Lewy body disease; pathogenesis; aggregation
Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.
Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.
Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.
Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.
Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.1306967
Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn). Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD). These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.
In this study, the authors examined whether rhythm metrics capable of distinguishing languages with high and low temporal stress contrast also can distinguish among control and dysarthric speakers of American English with perceptually distinct rhythm patterns.
Acoustic measures of vocalic and consonantal segment durations were obtained for speech samples from 55 speakers across 5 groups (hypokinetic, hyperkinetic, flaccid-spastic, ataxic dysarthrias, and controls). Segment durations were used to calculate standard and new rhythm metrics. Discriminant function analyses (DFAs) were used to determine which sets of predictor variables (rhythm metrics) best discriminated between groups (control vs. dysarthrias; and among the 4 dysarthrias). A cross-validation method was used to test the robustness of each original DFA.
The majority of classification functions were more than 80% successful in classifying speakers into their appropriate group. New metrics that combined successive vocalic and consonantal segments emerged as important predictor variables. DFAs pitting each dysarthria group against the combined others resulted in unique constellations of predictor variables that yielded high levels of classification accuracy. Conclusions: This study confirms the ability of rhythm metrics to distinguish control speech from dysarthrias and to discriminate dysarthria subtypes. Rhythm metrics show promise for use as a rational and objective clinical tool.
dysarthria; speech rhythm; rhythm metrics